The effect of myometrial invasion on prognostic factors and survival analysis in endometrial carcinoma

Background We investigated the relationship between myometrial invasion and the prognostic factors on overall and progression free survival in endometrial carcinoma. Methods 122 cases operated with endometrial cancer were included into the study. Progression-free survival and overall survival were evaluated according to degree of myometrial invasion. We also investigated the relationship between myometrial invasion and prognostic factors. Results The 5- year progression-free survival rate was 90 % in stage I, 66 % in stage II, 32 % in stage III and 60 % in stage IV. The 5- year overall survival rate was 95 % in stage I, 89 % in stage II, 49 % in stage III and 30 % in stage IV. The progression free survival and overall survival for patients with more than 50 % myometrial invasion were detected 67 % at 58 months and 66 % at 60 months, respectively. The clinicopathological variables that significantly correlated with myometrial invasion of more than 50 % were as follows: pelvic lymph node metastasis (p: 0,00029-OR: 11.2), cervical stromal invasion (p: 0008-OR:7.9), LVSI (p< 0.0001-OR: 16.5). Conclusion The depth of myometrial invasion is one of the most important prognostic indicators and determinants of therapy in endometrial cancer.


Introduction
Endometrial cancer affects mainly postmenopausal women. The average age of women diagnosed with endometrial cancer is 60. It is uncommon in women under the age of 45. In 2018, it is estimated that there will be 63,230 new cases of uterine cancer and an estimated 11,350 people will die of this disease 1 . These estimates include both endometrial cancers and uterine sarcomas. About 63,230 new cases of cancer of the uterine corpus will be diagnosed, but only about 5,058 of these cases will be uterine sarcomas. Up to 8% of uterine corpus cancers are sarcomas, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates 2 . Fortunately, the majority of women with endometrial cancer are diagnosed at an early stage (the disease is confined to the uterine corpus) and may be cured by surgery with or without adjuvant radiotherapy 3 . Survival is obviously stage related. According to a study by Creasman; the 5year progression-free survival rate was 92 % in stage I, 82 % in stage II, 68 % in stage III and 29 % in stage IV4. The 5-year overall survival rate was 89 % in stage I, 78 % in stage II, 61 % in stage III and 21 % in stage IV 4 . In endometrial carcinoma, myometrial invasion is a wellknown predictor of recurrence, and important in the decision making for adjuvant treatment 5 . The objective of this study was to analyze the effect of myometrial invasion on overall and progression free survival in endometrial carcinoma. The relationship between myometrial invasion and other known prognostic factors in endometrial cancer was also studied.

Material and methods
We reviewed the records of 122 endometrial carcinoma patients treated at University of Health Sciences, Haseki Training and Research Hospital, Department of Gynecology and Obstetrics, Division of Gynecologic Oncology. Ethics Committee Approval was taken from the local committee of our institution. All patients underwent staging procedures including total hysterectomy, adnexectomy, peritoneal washings for cytology, pelvic and para-aortic lymphadenectomy, and omentectomy if indicated. All cases were histologically confirmed as endometrioid adenocarcinoma, papillary serous carcinma, clear cell carcinoma, or carcinosarcoma, and were included in the study. All cases of endometrial stromal sarcoma and leiomyosarcoma were excluded. Progression-free survival (PFS) was defined as the period between the time of surgery and the observation of the recurrence. Overall survival (OS) was the time between the surgery and death, and follow-up time was evaluated as the time between the surgery and the time that the patient was last examined (death or last visit).

Statistical analysis
Data were analyzed using SPSS statistical software, version 11.5. Descriptive statistics were used to analyze demographic data and were summarized as numbers with percentage or median with range. Progression free survival (PFS), overall survival (OS) were analyzed by the Kaplan-Meier method. Comparisons of survival curves were performed using the log-rank test. The effect of myometrial invasion was analyzed taking into account other variables significantly linked to survival. Odds ratios and 95 % confidential intervals were used to assess the risk of myometrial invasion in relation to each pathological variable. P-values of <0.05 were considered significant.

Results
A total of 122 patients with endometrial cancer under-went primary surgery at our institution. The average age of patients was 58.5 ± 10 years (median 58; range 32 -86 years. All the patients underwent abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO). 109 patients underwent a hysterectomy and bilateral salpingo-oophorectomy with pelvic lymphadenectomy. Pelvic and/or para-aortic lymphadenectomy was performed in 19 patients.  Pelvic lymph node dissection was performed on a hundred-nine patients and both pelvic and para-aortic lymph node dissection was performed on nineteen patients. In total, 14 patients (11.4 %) had lymph node metastases. Eleven patients (n: 11/109, 10 %) had metastasis in the pelvic region, and three patients (n: 3/19, 15.7 %) had tumor in the para-aortic region. Seventeen patients (13.9 %) developed recurrences.

Recurrences
The recurrence was detected 17 patients. Recurrence was outside of the pelvic region in 6 patients.

The relationship between myometrial invasionprognostic factors
When patients with myometrial invasion of more than 50 %, pelvic lymph node metastasis, cervical involvement, LVSI, adnexal spread, peritoneal cytology positivity, and omental involvement were analyzed (

Discussion
In this study, we evaluated the relationship between myometrial invasion and prognostic factors-survival analysis.
Myometrial invasion was documented in 97 cases (79.5 %). Myometrial invasion was found 74.4 % in stage I cases. In the present study, the progression free survival and overall survival for patients with more than 50 % myometrial invasion were detected 67 % and 66 %, respectively. Recently, screening of biological indexes and gene therapies for endometrial carcinoma is becoming an active research field. Specific indicators of adverse outcomes are needed in order to tailor the management of endometrial cancer and improve their survival rates. During the last decades microcystic, elongated, fragmented (MELF) histologic pattern has been examined and proposed as a prognostic marker in patients with endometrial carcinoma 6 . Murray et al firstly described the MELF pattern of invasion in patients with endometrial adenocarcinoma 7 .
Significantly higher rates of myometrial invasion >50% were detected in patients with MELF compared to those with non-MELF 8 . Another study from Sanci et al reported significant impact on overall survival (OS) n patients with MELF pattern compared with those with MELF (-) 9 .
Tripartite motif containing 44 (TRIM44) has been demonstrated to be important in tumor metastasis and progression. High TRIM44 expression was associated with poor overall survival (OS) or disease-free survival (DFS) in EC patients 10 . High TRIM44 protein expression was significantly correlated with the FIGO stage, depth of myometrial invasion, histological grade and lymph node metastasis 10 . Myometrial invasion depth and lymph node involvement are also known to affect survival in endometrial carcinoma. In a large study carried out by Jones et al. five years' survival rates of patients with or without deep myometrial invasion were found as 60 % and 80 %, respectively 11 . Five years' survival rates of deep myometrial invasion in the literature were 71-88 % for grade I, 60-79 % for grade II and 32-65 % for grade III 12,13 . In the present study, the patients with myometrial invasion < 50 % was 88 % compared 67 % for the patients with myometrial invasion > 50 % at 5 year PFS (p:0,0013). The 5-year OS rate was 96 % for patients with myometrial invasion < 50 % versus 66 % for those with myometrial invasion > 50 % (p<0,0001). We found a significant difference between PFS rates of patients with and without myometrial invasion.
According to the prognostic parameters for endometrial carcinoma of the uterine factors include histological type, histological grade and depth of myometrial invasion, lymphovascular invasion, presence of atypical endometrial hyperplasia, cervical involvement, DNA ploidy and S-shape fraction and hormone receptor status. The extra-uterine factors include positive peritoneal cytology, adnexal involvement, pelvic and para-aortic lymph node metastasis and peritoneal metastasis 14,15 . For a patient with endometrial cancer, the presence of deep myometrial invasion is an important prognostic factor that strongly affects treatment planning and prognosis 5 . In this study, the prognostic value and relationship with clinicopathologic parameters of myometrial invasion were analyzed and compared.
The depth of myometrial invasion is a highly important factor that can be used to predict nodal metastasis 16 . Because of the higher prevalence of lymph node metastases, patients with depth of myometrial invasion are more likely to have a more extensive surgical lymph node assessment than patients with absence of myometrial invasion 17 . In present study, we found pelvic lymph node and para-aortic lymph node metastasis, 9 %, 2.4 %, respectively.
The patients with more than 50 % myometrial invasion on gross intraoperative examination of the uterus appear to have a six-to seven-fold higher prevalence of pelvic lymph node metastases, and advanced surgical stage compared with women with less than 50% invasion, patients with deep myometrial invasion on gross examination should be considered for more aggressive surgical staging, including pelvic and para-aortic lymphadenectomy 18 . Invasion to more than half of the myometrium in patients were significantly associated with cervical extension, positive peritoneal fluid cytology, adnexal, LVSI and pelvic lymph node involvement in present study. However, there was no statistically significant association between omental involvement. Previous studies showed that the tumor grade and the depth of myometrial invasion, as well as LVSI, are useful predictors for the risk of lymph node metastasis 12, 19 . Patients with more than 50 % gross myometrial invasion have a 6.4-fold higher prevalence of pelvic lymph node metastases and a 6.9-fold higher prevalence of para-aortic lymph node metastases than patients with less than 50 % myometrial invasion 21 . Creasman et al., reported that the incidence of para-aortic lymph nodal metastases increased from 2 % in patients with no myometrial invasion to 21 % with deep myometrial invasion 12 . In our study, statistically significant associations were found between deep myometrial invasion and pelvic lymph node involvement (OR: 11.2, p: 0,00029).
In the study of Ayhan et al., there were extra-abdominal metastases in 16 %; liver, spleen, or diaphragmatic spread in 24 %; small intestine involvement in 24 %; and large intestine involvement in 19% of the patients22. The recurrence rate in our present study was 37.5 % (17 patients) excluded stage I. The recurrence site was vaginal in 11 patients (64.7 %), abdominal skin in 1 patient (5.8 %), liver in 3 patients (17.6 %), and small intestine in 2 patients (11.7 %). This study had several limitations. The sample size was relatively small and the study was retrospective in nature. Despite this limitation, the primary strength of the study was that it was conducted in a single institution, where the pathological specimens are reviewed by experienced gynecologic pathologists. The size of our study cohort was sufficient for analyzing the prognostic factors that were independently associated with DFS and OS.

Conclusion
This single-center retrospective analysis confirms that myometrial invasion are important prognostic factors of progression-free survival and overall survival in patients diagnosed with endometrial cancer.